1. Field of the Invention
The invention relates to the preparation of halo nicotinic acid esters which are useful in preparing compounds having retinoid activity, e.g. 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate.
2. Background of the Art
6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate is a compound which is known to have retinoid activity, i.e. it is active at the same biological receptor as retinoic acid. This compound is disclosed in U.S. Pat. No. 5,089,509. In this patent, 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate is prepared by the reaction of 4,4-dimethyl-6-ethynyl-thiochroman and ethyl-6-chloronicotinate. In this patent ethyl-6-chloronicotinate is prepared by the reaction of 6-chloronicotinic acid and ethanol in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine, dissolved in methylene chloride. The yield in this preparation is only about 60% and the workup is very difficult. In addition, the reagents used in this synthesis (1,3-dicyclohexylcarbodimide and 4-dimethylaminopyridine) are identified as Highly Toxic (USA) and Toxic (European) (Source: Aldrich Material Data Safety [MDS] Sheet). As a result these reagents pose a considerable health risk before, during, and after the reaction is conducted. In U.S. Pat. No. 5,023,341, it is also disclosed that 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate may be prepared by the above reaction.
6-ethyl chloronicotinate is prepared from the corresponding 6-chloronicotinic acid and ethanol in U.S. Pat. No. 4,576,629. The nicotinate is utilized to prepare various herbicides. In this reference, a yield of 89% was obtained by means of a large excess of ethanol and sulfuric acid as the catalyst for the esterification reaction. This procedure requires a difficult separation of the product as well as requiring the handling of a very corrosive sulfuric acid reactant. Sulfuric acid is also identified as being Highly Toxic (MDS sheet). Further, it cannot be disposed of until it is neutralized with base. The procedure will result in added health risks and cost.
Chloronicotinic acid esters are also prepared by the reaction of 3-substituted pyridine-1-oxides with phosphoryl chloride. (See Yamanaka et al, Site-Selectivity in the Reaction of 3-Substituted Pyridine 1-Oxides with Phosphoryl Chloride; Chem. Pharm. Bull. 36(6)2244-2247(1988)). The procedure results in a mixture 2 and 6-chloronicotinic acid esters which must be separated to obtain the 6-chloronicotinic acid ester prepared according to the process of the present invention. Moreover, the 6-chloro is present as a minor component in the isomer mixture.
The unsubstituted compound, nicotinic acid, has been esterified by reaction with triethylorthoacetate at a yield of 80%. (See Trujillo et al, Facile Esterification of Sulfonic Acids and Carboxylic Acids with Triethylorthoacetate; Tetrahydro Letters, Vol. 34, No. 46, pp. 7355-7358, (1993)). Unexpectedly, the applicant's have achieved significantly higher yields in the esterification of halonicotinic acids.
Thus, it is clear that there is a continuing interest in preparing esters of both substituted and nonsubstituted nicotinic acid which are useful as intermediates to prepare retinoids as well as other compounds.
It is therefore one object in the invention to provide a method of preparing an ethyl-6-halonicotinate in high yield.
It is another object to the present invention to provide such ethyl-6-halonicotinate in a process wherein an excess of reactants are not required, the product is isolated without difficulty and no corrosive reactants are utilized.
Additional objects, advantages and features of the invention will become apparent to those skilled in the art from the following description.